Field of the Invention

The present invention relates to an enteric coated pellet composition comprises duloxetine hydrochloride as active ingredient and an enteric coating comprising cellulosic polymer in an amount range of 35 mg to 45 mg in total composition which is neutralized with at least one alkaline material to any degree from 85% to 95% of the acidic groups

Background of the Invention

Duloxetine is classified as a serotonin norepinephrine reuptake inhibitor (SNRI). The mechanism of action for Duloxetine is based on is the specific inhibition of both serotonin and norepinephrine reuptake, while it weakly inhibits dopamine reuptake besides, it has no significant affinity for histaminergic, dopaminergic, cholinergic or adrenergic receptors.

Chemical name of Duloxetine is (+)-(S)-N-methyl-gamma-(l-naphthyloxy)-2- thiophenepropylamine, and is commonly used as its hydrochloride salt. Duloxetine hydrochloride is a white to slightly brownish white solid, which is slightly soluble in water, its solubility is not pH dependent. The empirical formula is C18H19NOS, which corresponds to a molecular weight of 297.42 as is base and 333.88 as its hydrochloride salt. The structural formula of duloxetine is:

Formula I

The chemical structure of duloxetine hydrochloride is well characterised. It is an optically active molecule, which presents 1 asymmetric carbon, therefore two enantiomers are possible. The S enantiomer has been selected based on both in vitro and in vivo studies. Duloxetine is extensively metabolised by oxidative enzymes (CYP1A2 and the polymorphic CYP2D6), followed by conjugation. The pharmacokinetics of duloxetine demonstrate large inter-subject variability (generally 50-60%).

Duloxetine is well absorbed after oral administration with a maximum concentration occurring 6 hours post dose. The absolute oral bioavailability of duloxetine ranged from 32% to 80%

(mean of 50%). Food delays the time to reach the peak concentration from 6 to 10 hours and it marginally decreases the extent of absorption (approximately 11 %). Duloxetine is approximately 96% bound to human plasma proteins. Duloxetine is extensively metabolised and the metabolites are excreted principally in urine. The elimination half-life of duloxetine ranges from 8 to 17 hours (mean of 12 hours).

As being a member of selective serotonin reuptake inhibitors (SNRI) which inhibits specifically the reuptake of both serotonin and norepinephrine, duloxetine is used to treat depression particularly major depressive disorder.

Major depressive disorder is reported to be the most common mood disorder, with a lifetime prevalence of about 15% and as high as 25% in women.

In addition, duloxetine is also used in the treatment of peripheral diabetic neuropathy, generalized anxiety disorders, as well as the treatment of stress urinary incontinence in women.

The original medicinal product currently marketed in the form of capsule containing enteric- coated pellets under the name YENTREVE ^® in the strength of 20 mg and 40 mg was commercially authorized by the European Medicines Agency in August 2004 for moderate to severe stress urinary incontinence (SUI) in women.

YENTREVE ^® is in the form of hard gastro-resistant capsule contains duloxetine in the form of the hydrochloride salt that is equivalent to 20 and 40 mg of duloxetine and as an another original medicinal product, it is currently marketed in the form of capsule under the name of CYMBALTA ^® in the strengths of 30 mg and 60 mg, wherein product contains duloxetine in the form of the hydrochloride salt. CYMBALTA ^® is in the form of hard gastro-resistant capsule contains enteric coated pellets.

Prior art documents describe many enteric compositions of duloxetine and its pharmaceutically acceptable salt thereof. EP0693282 discloses a duloxetine containing enteric-coated pellet formulation comprising an enteric layer including hydroxypropylmethylcellulose acetate succinate (HPMCAS) as enteric polymer with neutralization degree in the range of 25% to 65% with ammonia.

W02008077939 discloses a pharmaceutical pellet composition comprising a duloxetine core and a separating layer in which a sodium chloride salt is used in the form of crystals.

EP2377525 discloses pellet composition comprising a core with duloxetine, an intermediate non-porous layer including one or more film forming water-soluble polymers that solubilizes the active substance, an enteric layer and an optional finishing layer.

EP1919467 discloses a duloxetine hydrochloride delayed release formulation comprising an inert core, a drug layer, a separating layer and an enteric layer including at least one methacrylic acid copolymer and hydroxypropyl methyl cellulose phthalate.

W02008020286 discloses a delayed release pharmaceutical composition comprising; a core with duloxetine, optionally a separating coat on the core and an enteric coat on the core or on the separating coat wherein the enteric coat comprises methacrylic acid copolymer.

EP3035919 discloses an enteric-coated tablet consisting of a core comprising duloxetine hydrochloride which is blended uniformly without the use of any liquid with the amount of said compressible sugar being 60-85% by weight calculated on the total weight of the core, and optionally with one or more pharmaceutically acceptable excipients, and an enteric coating layer which is applied directly on the core and comprises methacrylic acid-ethyl acrylate copolymer (1 : 1) as the only polymer resistant to gastric acid and one or more pharmaceutically acceptable excipients.

EP2453880 discloses an enteric duloxetine hydrochloride formulation in pellet form comprising a duloxetine containing core, particularly an inner protective layer coating the duloxetine core, further a separating layer and an enteric layer are applied respectively.

W02010078878 discloses a pharmaceutical dosage form consisting of of plurality of pellets comprise a pellet core with a diameter of 600-1000 micrometers, a drug layer covering the pellet core including duloxetine and binder which layer preferably constitutes 25-40 wt% of the total weight of the pellet, a seperating layer covering the drug layer including a binder and a pore forming component which layer preferably constitutes 3-10 wt% of the total weight of the pellet, and enteric coating layer covering the seprating layer including acid resistant polymer, which layer preferably constitutes 10-40 wt% of the total weight of the pellet.

EP2240173 discloses a pharmaceutical compositions comprising a core obtainable by wet granulation including an intimate mixture of duloxetine or pharmaceutically acceptable salts thereof having a micronized particle size wherein the core is covered with an enteric layer including hydroxypropyl methylcellulose phthalate and optionally one or more pharmaceutically acceptable excipients.

W02010037849 discloses an enteric pellet comprising; a core including duloxetine or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients; an intermediate non-porous layer including one or more film forming water-soluble polymers; an enteric coating layer including polyvinyl acetate phthalate as the enteric polymer, and an optional finishing layer.

EP2170297 discloses a pharmaceutical formulation comprising; a core including an amount of duloxetine, an enteric coating including hydroxypropyl methylcellulose phthalate and a separating layer including polyvinyl alcohol or optionally a cellulose polymer.

Although, it is already known duloxetine is labile in solution at pH values less than 2.5 due to degradation in the gastric environment generated with the acidic groups in enteric polymer structure and the natural environment of stomach after oral administration. Based on the invention, enteric coated dosage forms pass through the stomach unchanged and do not release the active substance until arriving small intestine.

The present invention relates to an enteric coated pellet comprising Duloxetine hydrochloride as active ingredient and an enteric layer with an optimized neutralization degree of the cellulosic polymer in a specific amount range.

SUMMARY OF THE INVENTION

The present invention discloses an enteric coated pellet comprises a pellet core, a drug layer with duloxetine hydrochloride, a separating layer, an enteric layer comprising hydroxypropyl methylcellulose acetate succinate, wherein the hydroxypropyl methylcellulose acetate succinate is neutralized to the degrees from 85% to 95% of the succinic acid groups with at least one alkaline material. The present invention also relates to the use of enteric coated pellets or pharmaceutical compositions comprising pellets according to the invention for the treatment of major depressive disorder, peripheral diabetic neuropathy, generalized anxiety disorders and moderate to severe stress urinary incontinence in women.

The present invention also relates to pharmaceutical compositions comprising an enteric coated pellet according to the invention.

The present invention relates to an enteric coated pellet which is composed of one pellet core and at least three different layers with different functions and pharmaceutically acceptable excipients.

The present invention is to provide an enteric coated pellet by using fluid bed processor.

One object of the present invention is to provide a manufacturing process of the enteric coated pellet comprising duloxetine hydrochloride wherein the process comprises the following steps: a pellet core; a drug layer coating the core, comprising duloxetine or a pharmaceutically acceptable salt thereof, especially duloxetine hydrochloride, and a coating polymer, filler and solvent; a separating layer coating the drug layer, comprising a coating polymer, filler, solvent and a pore forming component, an enteric layer coating the separating layer, comprising a plasticizer, filler, solvent, neutalization agent, cellulosic polymer. an optional finishing layer coating the enteric layer.

The present invention is related to an enteric coated pellet in which the enteric characterization is dependent on the neutralization process of acidic groups in the composition, particularly neutralization ratio of acidic groups in the enteric layer.

The present invention is to provide an enteric coated pellet comprises an inert core, a drug layer consisting of duloxetine hydrochloride and pharmaceutically acceptable excipients; a separating layer; an enteric layer comprising hydroxypropylmethylcellulose acetate succinate (HPMCAS) as celulosic polymer and pharmaceutically acceptable excipients; an optional finishing layer. The present invention is to provide an enteric pellet dosage comprising HPMCAS, talc as filler, aqueous ammonium hydroxide as neutralization agent, deionized water as solvent and triacetyl citrate as plasticizer in the enteric layer.

The present invention is to provide a pellet dosage form with the enteric layer, wherein the process comprises the following steps: i) Hydroxypropyl methylcellulose acetate succinate is dispersed in deionized water during stirring, ii) Aqueous ammonium hydroxide is added to the disperison obtained in Step (i) for neutralization process of acidic groups generated from HPMCAS till to observe pH values between 5.0 to 5.5, iii) Triethyl citrate and talc are added subsequently to the dispersion obtained in Step (ii) under stirring, iv) The dispersion obtained in Step (iii) is sprayed on the pellet core that had coated with drug layer and separating layer previously, v) Enteric coated pellets obtained in Step (iv) were dried.

In the present invention, neutralization process is performed to the degrees from 85% to 95% degree in a composition comprising from 35 mg to 45 mg of HPMCAS in the compositon.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an enteric coated pellet comprises a pellet core, a drug layer with duloxetine hydrochloride, a separating layer, an enteric layer comprising hydroxypropyl methylcellulose acetate succinate, and optionally a finishing layer, wherein the hydroxypropyl methylcellulose acetate succinate is partially neutralized with at least one alkaline material to any degree from 85% to 95%.

The present invention also provides an enteric coated pellet according to the invention or a pharmaceutical composition compises the pellet described in the invention, for use in the treatment of major depressive disorder, peripheral diabetic neuropathy, generalized anxiety disorders and moderate to severe stress urinary incontinence in women. In the present invention, the pellet core is a spherical core that may be made by pelletizing of pharmaceutically acceptable water soluble materials such as sugars or starches or mixtures thereof in a manner know by a skilled person in the art. Preferably the pellet core is sugar sphere which is covered by a drug layer. The drug layer comprises duloxetine hydrochloride with a pharmaceutically acceptable excipients. Further, drug layer is covered by a separating layer. Then, an enteric layer is coated on the drug layer. The design of a pellet is completed. A finishing layer could be applied optionally.

The present invention also provides a pharmaceutical composition comprising an enteric coated pellet according to the invention. Preferably, the composition is in capsule form.

In one of the embodiment, the composition comprises duloxetine hydrochloride equivalent to 20 mg to 60 mg duloxetine.

Duloxetine is known to have poor stability due to being incompatible with gastric juice that causes to decompase its easily in an acidic environment upon formation of a highly toxic naphthol moiety. Thus, an enteric coated pellet formulation is more desirable than a tablet.

In the present invention the term “enteric coated pellet” refers to a pharmceutical dosage form which is designed to pass unchanged in acid environment, such as stomach, and dissolves when it leaves the stomach and enters the near neutral environments such as the small intestine.

Moreover, duloxetine is known to tend to interact with the polymer in the enteric layer. Thus, in this present invention, the separating layer is applied on the drug layer besides to prevent of the unwanted interaction, in order to provide a smooth base for the application of the enteric layer and prolong the formulation's resistance to the acidic environment of the stomach, improve stability by minimizing the interaction between drug in the core and the enteric cellulosic polymer in the enteric layer from coming into direct contact with each other and also improve stability of drug from light exposure.

In one of the embodiment, process of preparing enteric layer is composed of preparing a dispersion of HPMCAS in the solvent, neutralization process of HPMCAS acidic groups with an alkaline material as the neutralization agent are performed, further filler and plasticizer are added to the dispersion and mix them all well to obtain an homogenous enteric layer compositon.

The enteric layer is the last layer of the enteric coated pellet composition that is comprised of an enteric cellulosic polymer, which must be chosen for compatibility with duloxetine. The polymer must be one having only a small number of carboxylic acid groups per unit weight or repeating unit of the polymer.

In a one of the preferred embodiment, the cellulosic polymer is hydroxypropylmethylcellulose acetate succinate (HPMCAS), which product is defined as containing not less than 4% and not more than 28% of succinoyl groups, which are the only free carboxylic groups in the compound.

The solubility of HPMCAS is a pH-dependent polymer in aqueous liquids due to its succinate groups. In the acidic environments, HPMCAS is protonated and insoluble. But, in the higher pH environments, it undergoes deprotonation and becomes soluble. The onset of aqueous solubility of HPMCAS is in a pH range of 5.5 - 6.8.

In one of the embodiment, the amount of HPMCAS used in the enteric layer is in range of 35 mg to 45 mg.

In another embodiment, the alkaline material is selected from aqueous solution of sodium hydroxide, aqueous solution of potassium hydroxide, aqueous solution of ammonium hydroxide, and mixtures thereof. Preferably, the alkaline material is the aqueous ammonium hydroxide.

In a preffered embodiment, the neutalization agent used in enteric layer is aqueous ammonium hydroxide at 25% concentration.

Solvent is used to obtain a dispersion containing triethyl citrate, the preferred HPMCAS, talc and aqueous ammonium hydroxide. Preferably, the solvent is deionized water.

In one of the embodiment, hydroxypropyl methylcellulose acetate succinate is partially neutralized with at least one alkaline material to any degree from 85% to 95% of the succinic acid groups. The term "partially neutralized" indicate that only a portion of the succinic acid groups present in the HPMCAS polymer is neutralized with an alkaline material (such as a base), and the rest of the succinic acid groups remain in the acid form.

In one of the embodiment, partial neutralization may impact the enteric properties of the composition with direct impact on dissolution.

Example 1, as enteric coated pellet prepared according to the processes stated above were subjected to in vitro dissolution study. The conditions of dissolution study are set by US FDA, based on the information dissolution is performed in 0.1N HC1 for 2 hours and then in pH 6.8 phosphate buffer for 60 minutes. The volume of dissolution media is 1000 ml, temperature is 37°C±0.5°C, rotation speed is 100 rpm, apparatus is paddle. Table 1: Comparative dissolution profiles for Example 1 and Reference drug product

Dissolution results were compared according to the Guideline on the Investigation of Bioequivalence, the similarity index Ϊ2 parameter should be higher than 50 to be similar with reference drug product. In the present invention, the similarity factor Ϊ2 of Example 1 was calculated as 55.8 which means the release profile of developed formulation is similar to reference drug product.

In this present invention, an enteric coated pellet composition comprising duloxetine hydrochloride as active ingredient has en enteric coating composed of partially neutralized HPMCAS with aqueous ammonium hydroxide to the degree between 85% to 95% in an amount range of 35 mg to 45 mg.

While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.